Long-term bone marrow cultures (LTBMC) contain two major cell populations referred to as compartments. The hematopoietic stem cell compartment, contains cells at various stages of self renewal capacity and differentiation and the adherent cell or stromal cell compartment has been shown to provide the environment necessary for the production and differentiation of hematopoietic stem cells and their progenitors. Both compartments interact to facilitate hematopoiesis in vitro (Naparstek, et al; Exp. Hematol. 13: 701-708 (1985).
Bone marrow transplants are widely used for treating congenital disorders of the bone marrow or hematopoietic stem cell, e.g. aplastic anemia, acute leukemias, recurrent lymphomas, or solid tumors. Prior to receiving a bone marrow transplant, the recipient is prepared by ablating or removing endogenous recipient hematopoietic stem cells. This preparation is usually carried out by total body irradiation or delivery of a high dose of an alkylating agent or other chemotherapeutic cytotoxic agents (Greenberger, J. S., Br. J. Hematol, 62: 606-605, 1986; Anklesaria, P., et al, PNAS, USA, 84: 7681-7685, 1987; Thomas, E. D., Cancer, 49: 1963, 1982; Thomas, E. D., N. Eng. J. Med., 292: 832-843, 895-902, 1975). Following preparation of the recipient, donor bone marrow cells are injected intravenously and have been demonstrated to home to multiple sites within the recipient where they proliferate and reconstitute all elements of the hematopoietic stem cell compartment including neutrophilic granulocytes, megakaryocytes (platelets), red blood cell progenitors leading to mature erythrocytes, T-lymphocytes, B-lymphocytes, monocyte/macrophages, basophils and mast cells (Thomas, E. D., cited supra). Some data from several clinical transplanation centers suggest that donor origin stromal cells of the hematopoietic microenvironment are also detected in small numbers in recipients after marrow transplant (Thomas, E. D., cited supra).
Two general categories of marrow transplanation have been described. In an allogeneic transplant, HLA tissue typing is carried out on various marrow donors and a matched marrow specimen as close as possible to that of the recipient, is used as the donor cell population. Allogeneic marrow transplant is the most common form of transplant in patients with malignancy of the marrow compartment where removal of the malignant cells from the marrow is a very difficult process (Thomas, E. D., cited supra).
The other category of bone marrow transplant is autologous marrow transplant. An autologous marrow transplant involves removal of the patient's own bone marrow and washing or preparing it by techniques that remove unwanted populations of cells (including tumor cells). The washed cells are then reinfused into the patient after the preparative regimen is completed. Under these conditions, the problems of graft versus host disease, or rejection of non-matched marrow can be reduced or eliminated. Thus, there is a decreased risk of infection or graft failure.
Autologous marrow transplant is gaining popularity and frequency throughout the United States and Europe for the treatment of solid tumors or recurrent lymphomas. For these treatments, higher doses of chemotherapy and radiation therapy can be delivered. For this technique, there must be a source of untreated marrow available to give back to the patient. Autologous marrow transplant is generally the safer form of bone marrow transplantation because it overcomes many of the immune, histocompatibility, and rejection problems. Further, an autologous marrow transplant requires less of a support facility for a new hospital or treatment center setting up such a program (Thomas, E. D., cited supra).
Graft failure is a common complication of marrow transplantation with both autologous and allogeneic protocols (Thomas, E. D., cited supra). The mechanism of graft failure has been studied for many years. Clinical research data presented at national and international meetings over the last ten years has pointed toward a defect in bone marrow stroma as the cause of graft failure. Such a defect in marrow stroma may be attributable to the preparative regimen of total body irradiation and/or chemotherapy that is used to prepare the patient for the transplant (autologous or allogeneic). In some diseases, such as chronic myelogenous leukemia, a defect in marrow stroma can be an inherent part of the disease process.